Due to disease or trauma, surgeons need to replace bone tissue. They can use bone grafts (autografts or allografts) or synthetic materials to replace bone during surgery. Amongst the types of synthetic materials used to replace bone, surgeons use metals (e.g. stainless steel hip or knee implants), polymers (e.g. polyethylene in acetabular cups), ceramics (e.g. hydroxyapatite as a macroporous bone graft) or inorganic-organic composites (e.g. hydroxyapatite-poly(lactic acid) composites for fixation plates).
Calcium phosphate ceramics, such as hydroxyapatite or tricalcium phosphate, which are utilised as bone graft materials are typically produced by forming a macroporous structure, similar to that of cancellous bone. Such bone grafts typically have large values of total porosity (60-90%) with the porosity existing as a mixture of macropores (0.1 to 1 mm in size) and micropores (0.5 to 10 μm), with the macropores interconnected. These usually require high sintering temperatures, typically between 1100-1300° C., as part of the manufacturing process, to densify the calcium phosphates making up the porous ‘cancellous’ structure. Such a macroporous bone graft, typically used in granular form, is classed as osteoconductive, meaning that it acts as a scaffold and allows bone to grow along its surface. Unlike autografts, most synthetic calcium phosphate bone grafts are not osteoinductive. Osteoinductivity is the ability to induce new bone formation by directing undifferentiated mesenchymal stem cells to differentiate and form bone. Recently, some groups have reported developments of synthetic bone grafts based on calcium phosphates that are osteoinductive. The accepted test for osteoinductivity is the implanting of the bone graft material in a non-osseous (non-bone) site, either subcutaneously or intramuscularly in a suitable animal model, and using histology and histomorphometry determine if bone is formed in this site. A bone graft material that is only osteoconductive does not form bone in this site, whereas an osteoinductive material does form bone. The advantage of an osteoinductive bone graft is that, when implanted into a bone defect in humans, it will have an accelerated rate of bone repair because bone can form at the interface of the implant and host bone by an osteoconductive response, and also throughout the implant by an osteoinductive response. For new bone to form throughout an osteoconductive bone graft requires a longer time after implantation, as new bone migrates throughout the bone graft from the interface of the implant and host bone.
Osteoinductive calcium phosphate ceramics are disclosed in U.S. Pat. No. 6,511,510, describing calcium phosphate ceramics with a mixture of macropores with sizes between 0.1 to 1.5 mm and micropores with sizes between 0.05 to 20 μm, with a total porosity of between 20 and 90%, and a crystal size between 50 nm and 20 μm. These osteoinductive ceramics were formed using elevated temperatures of 1000-1275° C., preferably 1150-1250° C. The ceramic material is implanted as a block.
An osteoinductive calcium phosphate consisting essentially of microparticles with only micropores was described in US 2010/0034865 (U.S. Pat. No. 7,942,934), having micropores with sizes between 0.1 to 1.5 μm, with a surface area percentage of micropores of between 10 and 40% over the total surface of the granules, and a grain (crystal) size between 0.1 and 1.5 μm. These osteoinductive ceramics were formed using elevated temperatures of 1050-1150° C. In this patent, an example of granules that showed an osteoinductive response when implanted into the muscles of dogs that had the smallest micropores and grain (crystal) size was a tricalcium phosphate sintered at 1050° C.; values were reported as 0.58 μm pore size and 0.76 μm grain size, with a surface area percentage of micropores of 24.2%.
An inorganic resorbable bone substitute material with crystallites that are loosely held together rather than sintered together is described in DE 10060036. This material has a porosity consisting of three different size scales, with pores in the nanometer range, in the range of a few microns, and in the region of 100 to 1000 μm. The further disclosure US2007/0059379 (republished as US 2008/0152723) mentions the material described in DE 10060036, and combines calcium phosphate with a silica xerogel to form an inorganic resorbable bone substitute material that was stronger than the xerogel-free material. The silica xerogel has granule size of 1 to 1000 μm and the calcium phosphate has crystal size between 10 and 2000 nm. The xerogel has pores in the region of 0.5 to 20 nm, representing porosity of between 10 and 60%.
WO 2010/079316 describes an inorganic silicate-substituted calcium phosphate hydroxyapatite, which has the function of releasing high levels of silicon on soaking in solution, in order to stimulate formation of new bone. The CaP molar ratio is in the range 2.05 to 2.55 and the Ca/(P+Si) molar ratio is less than 1.66. The material is unsintered, and is used as a powder or a compacted powder. It is made by filtering a suspension of the compound, drying of the wet filter cake, grinding the dried cake to a fine powder and heating the powder at 900° C. Osteoinductivity was not tested.
US 2005/0191226-A1 (Tuan et al)—relates to a method for preparing hydroxylapatite powder. The hydroxylapatite powder was obtained by heating fish scales to temperatures including 600° C., 700° C., or 900° C. to remove the organic component and collecting the inorganic powder. The disclosure further relates to a hydroxylapatite porous body, which was obtained by sintering the hydroxylapatite powder. Osteoinductivity was not tested.
Grossin et al—(2010) “Biomimetic apatite sintered at very low temperature by spark plasma sintering: Physico-chemistry and microstructure aspects”. Acta Biomaterialia, vol. 6 (no 2). pp. 577-585 relates to spark plasma sintering, which was used to consolidate nanocrystalline apatites at non-conventional, very low temperatures (T<300° C.) so as to preserve the surface hydrated layer present on the nanocrystals. Bioceramic monoliths rather than granules were obtained.
U.S. Pat. No. 6,689,375 B1 (Wahlig et al)—relates to a resorbable bone implant material and method for producing the same. The powdery component of the implant material consists essentially of a mixture of hydroxyl apatite powder and calcium sulfate powder, wherein the hydroxyl apatite powder consists of synthetically prepared, precipitated crystalline nanoparticles, reported as having a crystal size of 10-20 nm width and 50-60 nm length. The specific absorbing BET surface area of the nanocrystals is reportedly, preferably, 100-150 m2/g.
U.S. Pat. No. 6,013,591 (Ying et al) relates to methods for synthesis of nanocrystalline apatites. The disclosure reports a series of specific reaction parameters that can purportedly be adjusted to tailor the properties of the recovered product. Particulate apatite compositions having average crystal size of less than 150 nm are reportedly provided. It is stated that products can have a surface area of at least 40 m2/g. Stated utilities for compositions are as prosthetic implants and coatings for prosthetic implants.